Summary

Cetuximab is used in alone or in combination therapy to treat advanced squamous cell carcinoma of the head and neck and to treat K-Ras mutation-negative, EGFR expressing metastatic colorectal cancer. In cases of colorectal cancer, the label states "Determine K-Ras mutation and EGFR-expression status using FDA-approved tests prior to initiating treatment."

Summary

The FDA-approved drug label for gefinitib states that it is indicated for first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test. The label also notes the potential clinical importance of considering CYP2D6 phenotype, though CYP2D6 testing is not mentioned.

Summary

The FDA-approved drug label for osimertinib states that it is indicated for the treatment of patients with metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC), as detected by an FDA-approved test, who have progressed on or after EGFR TKI therapy.

Summary

The panitumumab drug label contains information about EGFR-expressing metastatic colorectal carcinoma with disease progression on or following certain chemotherapy regimens. Detection of EGFR protein expression is necessary for selection of patients appropriate for Vectibix therapy. The label was updated to include information about treatment of patients with KRAS mutations. Retrospective subset analyses of metastatic colorectal cancer trials have not shown a treatment benefit for Vectibix in patients whose tumors had KRAS mutations in codon 12 or 13. Use of Vectibix is not recommended for the treatment of colorectal cancer with these mutations.

Summary

The FDA-approved drug label for regorafenib (Stivarga) states that it is intended for patients with metastatic colorectal cancer who were previously given fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if they were KRAS wild type, an anti-EGFR therapy. The label does not specifically mention any form of genetic testing. This drug-biomarker pair was previously in the FDA's "Table of Pharmacogenomic Biomarkers in Drug Labels" but has subsequently been removed.

Summary

Afatinib (GIOTRIF) is indicated in adult patients with non-small cell lung cancer with activating EGFR mutations. The EMA European Public Assessment Report (EPAR) for afatinib (GIOTRIF) states that EGFR mutation status should be established before initiation of afatinib therapy using a well-validated and robust methodology.

Summary

The EMA European Public Assessment Report (EPAR) highlights information regarding the contraindication of Cetuximab (Erbitux) in colorectal cancer patients with tumors with KRAS mutations or if tumor status is not known.

Summary

The EMA European Public Assessment Report (EPAR) requires testing tumours for EGFR mutations in patients with non-small cell lung cancer prior to treatment with erlotinib and recommends using a well-validated method of testing. The drug should be used with caution in patients with low expression of UGT1A1 or Gilbert's disease (caused by genetic variants in UGT1A1 gene), due to the inhibitory effects of erlotinib on glucuronidation by UGT1A1 (UGT1A1 genetic testing is not required).

Summary

The EMA European Public Assessment Report (EPAR) contains biomarker information regarding the indication of gefitinib (Iressa) in patients with tumors that have activating EGFR mutations, due to its mechanism of action.

Summary

The PMDA package insert for cetuximab (ERBITUX) states that it is indicated for individuals with epidermal growth factor receptor (EGFR)-positive, progressive or recurrent colorectal cancer that is refractory and inoperable. It also notes that K-Ras mutational status should be considered when selecting patients.

Summary

The PMDA package insert for erlotinib states that it is indicated for recurrent and/or advanced inoperable non-small cell lung cancer that is positive for an EGFR gene mutation and has not been previously treated with chemotherapy.

Summary

The PMDA package insert for gefitinib (Iressa) states that patients should be tested for EGFR gene mutations prior to administration. It also discusses the role of CYP2D6 is the metabolism of gefitinib.

Summary

The product monograph for afatinib (GIOTRIF) states that it is indicated for the treatment of patients with metastatic adenocarcinoma of the lung with activating EGFR mutation(s), including exon 19 deletions and the exon 21 L858R point mutation. A validated test is required to identify EGFR mutation status.

Summary

The product monograph for panitumumab (VECTIBIX) states that it is indicated for patients with EGFR-expressing metastatic colorectal carcinoma (mCRC) with wild-type KRAS, and should not be used in patients with KRAS-mutant mCRC or for whom KRAS mutation status is unknown.

Clinical Variants that meet the highest level of criteria, manually curated by PharmGKB, are shown below.
Please follow the link in the "Position" column for more information about a particular variant. Each link
in the "Position" column leads to the corresponding PharmGKB Variant Page. The Variant Page contains summary
data, including PharmGKB manually curated information about variant-drug pairs based on individual PubMed
publications. The PMIDs for these PubMed publications can be found on the Variant Page.

To see more Clinical Variants with lower levels of criteria, click the button at the bottom of the table.

Disclaimer:
The PharmGKB's clinical annotations reflect expert consensus based on clinical evidence and peer-reviewed
literature available at the time they are written and are intended only to assist clinicians in decision-making
and to identify questions for further research. New evidence may have emerged since the time an annotation was
submitted to the PharmGKB. The annotations are limited in scope and are not applicable to interventions or
diseases that are not specifically identified.

The annotations do not account for individual variations among patients, and cannot be considered inclusive of all
proper methods of care or exclusive of other treatments. It remains the responsibility of the health-care provider
to determine the best course of treatment for a patient. Adherence to any guideline is voluntary, with the
ultimate determination regarding its application to be made solely by the clinician and the patient. PharmGKB
assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of
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? = Mouse-over for quick help

The table below contains information about pharmacogenomic variants on PharmGKB. Please follow the link in the
"Variant" column for more information about a particular variant. Each link in the "Variant" column leads to
the corresponding PharmGKB Variant Page. The Variant Page contains summary data, including PharmGKB manually
curated information about variant-drug pairs based on individual PubMed publications. The PMIDs for these
PubMed publications can be found on the Variant Page.

The tags in the first column of the table indicate what type of information can be found on the corresponding
Variant Page on the appropriate tab.

Visualization

†
The mRNA boundaries are calculated using the gene's default feature set from NCBI, mapped
onto the UCSC Golden Path. PharmGKB sets gene boundaries by expanding the mRNA boundaries
by no less than 10,000 bases upstream (5') and 3,000 bases downstream (3') to allow for
potential regulatory regions.

Introduction

Epidermal growth factor receptor (EGFR) encodes a transmembrane glycoprotein. This protein is a member of the protein kinase superfamily, which consists of EGFR (ErbB1/HER1), HER2 (ErbB2), HER3 (ErbB3) and HER4 (ErbB4). All family members contain an extracellular ligand-binding domain, a single membrane-spanning region, a juxtamembrane nuclear localization signal, and a cytoplasmic tyrosine kinase domain. They are collectively called as HER receptors and are ubiquitously expressed in various cell types, but primarily in those of epithelial, mesenchymal and neuronal origin. Under homeostatic conditions, receptor activation is tightly regulated by the availability of ligands, which together form the epidermal growth factor (EGF) family [Article:11252954]. From those ligands, EGF, transforming growth factor alpha and amphiregulin bind specifically to EGFR [Article:15864276]. Binding of the EGFR or other family members to a ligand induces receptor dimerization and tyrosine autophosphorylation and leads to cell proliferation. The EGFR involvement in carcinogenesis has been well established and mutations in EGFR can be utilized as predictive markers in the treatment of cancer.

EGFR Gene, Molecular Structure and Function

EGFR maps on chromosome 7p11.2, it covers 188.3 kb, from 55,086,725 to 55,275,031, on the positive strand. EGFR is composed of 28 exons and encodes a protein of 1210 amino acids (ENST00000275493, Ensembl v69) [Article:11752248]. Multiple alternatively spliced transcript variants that encode different protein isoforms have been found [Article:16925834].

EGRF activation by binding of growth factor leads to the autophosphorylation of the intracellular tyrosine kinase domain and results in the formation of receptor homodimers or heterodimers with other HER family members, and the tyrosine phosphorylated residues act as a docking site for various adapter molecules, and resulting in the activation of the downstream signaling pathways [Articles:18375904, 12648464], driving different biological processes including cell cycle progression and differentiation, increased cell invasiveness, apoptosis and angiogenesis [Articles:16014887, 11129168]. Thus, overexpression of EGFR is believed to have a critical role in tumor progression [Articles:16014887, 11129168, 16377102].

The principal cause of cancer-related mortality is lung cancer, and non-small cell lung cancer (NSCLC) constitutes almost 80% of all lung cases. NSCLC is arisen from lung epithelial cells, and comprises diverse histological subtypes including adenocarcinoma, bronchioloalveolar, squamous, anaplastic and large-cell carcinomas, about half of the NSCLC patients manifest advance disease at the time of diagnosis thus making the treatment difficult [Article:18287387]. Various oncogenic mechanisms, including EGFR gene mutations, increased EGFR copy number and EGFR protein overexpression may impair the regulation of tyrosine kinase activity of EGFR in tumor cells [Articles:18337605, 20388064] and may result in increased malignant cell survival, proliferation, invasion and metastasis [Article:19138950]. The current approach is that patients with specific types and stages of cancer should be treated according to standardized, predetermined protocols [Article:22594511]. However, understanding the molecular genesis of NSCLC and advances in the field of pharmacogenomics can lead to a rational use of targeted therapies.

EGFR as cancer drug target

EGFR has been linked to the growth of many human epithelial malignancies, including NSCLC, metastatic colorectal cancer (CRC), head and neck squamous-cell carcinoma (HNSCC), and pancreatic cancer [Articles:16377102, 20551942, 18681783]. Intensive laboratory and clinical research have facilitated development of EGFR inhibitors. There are two main types of EGFR inhibitors; tyrosine kinase inhibitors and monoclonal antibodies against EGFR (http://pharmgkb.org/pathway/PA162356267).

The FDA approved gefitinib through an accelerated process in May 2003 as monotherapy for the treatment advanced NSCLC patients after failure of both platinum-based and docetaxel chemotherapies. As a condition of accelerated approval, the FDA required demonstration of a survival benefit in a subsequent clinical trial. Three large, prospective studies showed no improvement in overall survival [Articles:14990632, 14990633, 16257339], therefore the original FDA approval for gefitinib was modified. Currently gefitinib is indicated as monotherapy for the continued treatment of advanced NSCLC patients after failure of both platinum-based and docetaxel chemotherapies who are benefiting or have benefited from gefitinib (http://dailymed.nlm.nih.gov/dailymed/).

Erlotinib monotherapy is indicated for the treatment of advanced NSCLC patients after failure of prior chemotherapy regimen. FDA also approved erlotinib in combination with gemcitabine for advanced pancreatic cancer patients who have not received previous chemotherapy (http://dailymed.nlm.nih.gov/dailymed/).

Previously, treatment outcomes of erlotinib or gefitinib were studied in unselected patients presenting conflicting results depending on the type of patient population enrolled in each study. However, the discovery that response to erlotinib or gefitinib is associated with the presence of activating somatic EGFR mutations in NSCLC has led to the design of clinical trials in which patients were selected on the basis of the EGFR mutational status [Articles:22594511, 23022519]. This pharmacogenetic approach and its results will be discussed in detail below.

Other TKIs (lapatinib, neratinib, pelitinib and vandetanib) were either approved or in clinical trial phases for cancers other than NSCLC (http://dailymed.nlm.nih.gov/dailymed/). Several clinical trials are continuing for afatinib and preliminary result of one of these trials will be discussed in the context of treatment of advanced NSCLC harboring activating somatic EGFR mutations.

Monoclonal antibodies: Cetuximab and panitumumab are monoclonal antibodies that specifically target the extracellular domain of EGFR. Cetuximab functions by blocking endogenous ligand binding to the extracellular domain of EGFR and enhances receptor internalization and degradation [Articles:6298788, 11255078]. Cetuximab and panitumumab were approved for the treatment of patients, other than NSCLC, with EGFR-expressing metastatic CRC refractory to chemotherapy [Articles:18316547, 19339720, 18003960]. Cetuximab was also approved for the treatment of advanced HNSCC in combination with radiation therapy [Articles:18784101, 16467544]. Since cetuximab and panitumumab block extracellular domain of EGFR, not TK domain, activating mutations might not affect treatment outcome.

Out of 68,986 unique samples deposited in the COSMIC database for EGFR (partial or full sequence and genotype data) including all cancers examined, 13,201 (19.1%) samples had somatic mutations and about 1.3% of all samples has more than one mutation. There are 842 unique location entries for somatic EGFR mutations. Among the mutation bearing patients, six of the mutations have a frequency >= 1% and five has 0.1%-1% frequency, remaining somatic mutations were spread out along EGFR, mostly missense substitutions but there are insertions and deletions as well. All six common somatic mutations (>= 1%) constitutes ~93% of all mutations and are in the tyrosine kinase domain (between 712 and 968 amino acids, exon 18-24) of EGFR (Table 1). The most common one is exon 19 (codon 729-761) mutations, essentially it is not a simple mutation, rather collection of different deletions and a few missense substitutions concentrated on codons 744-753 of exon 19, the most frequent one of this group is E746_A750del mutation. Exon 19 mutations comprise 48.3% of all mutations.

The second common mutation is L858R (rs121434568, T-to-G change at middle base of the codon) and comprises 36.2% of all mutations. Other missense mutations were also observed on this codon in different base(s) as monoallelic or biallelic mutation combinations (L858K, L858M, L858Q, L858R and L858L) in one or few subjects. The third common mutation, T790M (rs121434569) is detected in 3.8% of all mutations. The forth common is exon 20 mutations, a group of different insertions were concentrated at codons 763-774 and this group comprises 2.3% of all mutations. The fifth common one is observed at codon 719; mutation at the first base of codon 719 is in dbSNP as rs28929495 (G719S/G719C) and second base mutations give rise to G719A or G719D; all 719 codon mutations comprises 1.6% of all mutations. The last common mutation, L861Q (rs121913444) comprises ~1% of all mutations. L861R and L861V mutations were also observed on this codon in one or few subjects. The five rare mutations (0.1%-1% frequency) are A289V, G598V, E709K, S768I and L833V; and totaling ~1% of all mutations (Table 1).

Table 1: Incidence of the Common (¿1%) and Rare (0.1%-1% ) Specific Somatic Mutations of EGFR.

Mutation

Incidence*

Exon 19 mutations: Collection of different deletions and a few missense substitutions, the most frequent one is E746_A750del

48.3%

L858R (rs121434568). Other missense mutations were also observed on this codon in extremely low frequency

Exon 20 mutations: A group of different insertions concentrated at codons 763-774

2.3%

Codon 719 mutation: Mutation at the first base of codon G719S or G719C (rs28929495), 0.82%; Mutation at the second base of codon G719A or G719D, 0.77%

1.6%

L861Q (rs121913444). L861R and L861V mutations were also observed on this codon in extremely low frequency

~1.0%

A289V, G598V, E709K, S768I and L833V: combined incidence

~1.0%

*Incidences are derived from COSMIC database. 68,986 unique samples are deposited for EGFR of which 69% of are from lung cancer tissues

.

TK domain of EGFR (exon 18-21) was sequenced or assayed by TaqMan probes for known mutations in other than lung cancers. Although EGFR somatic mutations were not observed in many cancer tissues [Articles:15741570, 16199108, 16353180, 22252115, 22426987], when systematic approaches with more samples were collected as in COSMIC database [Article:20952405], mutations were observed in other cancers tissues. For the EGFR mutations in COSMIC database, the majority of the samples (69% of 68,986 unique samples) are derived from lung cancer tissues and remaining samples are derived from 38 different cancer tissues. EGFR mutations are observed at 7.4% of the lung cancer samples and 1-2% of salivary gland, eye, peritoneum, upper aerodigestive tract, adrenal gland, and thyroid cancer tissues. Of the 39 cancer tissue results deposited, 22 of them have EGFR mutations ranging from 0.1% (pancreas, hematopoietic and stomach tissues) to 7.4% (lung) of their respective tissues.

In a recent study, whole exome and genome sequences of 183 lung adenocarcinoma tumor/normal DNA pairs were analyzed and EGFR mutations were observed at 17.5% of patients with a few of them having more than one mutation. The L858R (rs121434568) and exon 19 deletions constituted half of the EGFR mutations [Article:22980975]. In contrast, whole exome sequencing of 31 NSCLC revealed a L858R mutation in only one patient (3.2%) [Article:22510280]. Several somatic mutations were also observed in genes other than EGFR [Articles:22980975, 22510280].

L858R (rs121434568) and exon 19 deletions:EGFR mutations that lead to increased response to epidermal growth factors are called activating mutations, thus having these mutations produce a more significant and persistent activation of intracellular signaling pathways, resulting in increased cell proliferation. On the other hand, lower concentrations of TKIs are required to inhibit TK phosphorylation, because the mutant receptor has reduced ATP affinity that accounts for increased sensitive to drugs as compared with wild type EGFR [Articles:16014887, 15118073, 19147750]. EGFR kinase domain mutations that are clustered around the ATP-binding pocket of the enzyme exon 19 mutations, L858R, G719X (G719C, G719S and G719A) and L861Q increase the kinase activity of EGFR therefore they are activating mutations [Articles:15118073, 19147750]. There are many rare mutations in this region that their functionalities have not been determined. The L858R and exon 19 mutations constitutes ~84.5% of COSMIC, 86.7% [Article:18670300] and 90.9% [Article:17888036] of all mutations, therefore many studies utilize these two mutations in their analysis.

Although prospective studies did not demonstrate increased overall survival [Articles:14990632, 14990633, 16257339] as first-line treatment for NSCLC, several trials have confirmed their clinical usefulness as second- or third-line therapy in advanced NSCLC based on longer progression free survival (PFS) and lower toxicity obtained with TKIs as compared to standard therapy [Articles:16014882, 19027483]. However, clinical responses to both erlotinib and gefitinib differ among NSCLC patients, approximately 10% of patients had clinical responses when treated with TKIs [Articles:14990632, 14990633, 16257339, 16014882, 19027483]. Sequencing of the EGFR in tumor samples from these responders showed somatic gain-of-function (e.g. activating) mutations and this guide to the new clinical trials or retrospective analysis in which patients were chosen depending on the activating EGFR mutational status [Articles:22594511, 23022519].

Having better clinical output with TKIs in patients with activating EGFR mutations led to new clinical trial design. In prospective phase III randomized trials comparing TKIs and chemotherapy as first-line therapy in patients with advanced NSCLC harbouring activating EGFR mutations, erlotinib [Article:21783417] gefitinib [Articles:20022809, 20573926] and afatinib treatment arms had significantly increased RR and longer PFS time, whereas OS did not show any clinical benefits when compared to standard chemotherapy [Articles:21783417, 20022809, 20573926]. Similarly, in a phase III trial where previously untreated East Asian NSCLC patients who were nonsmoker/former light smokers and treated with gefinitib or carboplatin/paclitaxel (IPASS trial), activating mutation harboring patients treated with gefitinib had significantly longer PFS time compared to carboplatin/paclitaxel group; on the contrary, EGFR mutation negative group had significantly shorter PFS time when treated with gefinitib [Articles:19692680, 21670455]. OS did not differ between two treatments arm (gefitinb vs. carboplatin/paclitaxel)[Article:21670455].

Few studies compared the clinical benefits of common L858R (rs121434568) and exon 19 mutations and failed to show any differential benefits [Articles:21670455, 17106442, 17610986, 16785471] between two types of mutations, except one small study suggested exon 19 deletions group had longer PFS compared to L858R in TKIs treated NSCLC patients [Article:21725039].

Demographic differences of the incidence of EGFR mutations in NSCLC patients were observed. Activating mutations in EGFR are more frequent in women (38% vs. 10% in man), nonsmokers (47% vs. 7% in smokers), adenocarcinomas (30% vs. 2% in non-adenocarcinoma) and Asian populations (26-36% vs. 7-12% in Whites) [Articles:20952405, 19147750, 17888036, 16850125]. EGFR mutations in all NSCLC patients (whether smokers or not) will be important, as inhibition of this receptor has considerable clinical benefits [Article:16850125]. This observation was particularly clear in Asian patients with EGFR mutations treated with gefitinib in the IPASS trial [Article:19692680].

T790M (rs121434569): Acquired resistance to TKIs: The majority of patients with an activating EGFR mutation received clinical benefits when treated with erlotinib/gefitinib, but the magnitude and the duration of the clinical response significantly vary among NSCLC patients [Articles:22594511, 23022519]. Mutation type (L858R vs. exon 19 del) seems to have little effect on the clinical outcome [Articles:21670455, 17106442, 17610986, 16785471]. However, majority of the NSCLC patients will develop resistance to erlotinib/gefitinib treatment and progress, this situation greatly limits the ability of these drugs to significantly prolong patient survival [Articles:22594511, 23022519].

The most frequent mechanism of acquired resistance to TKIs is the T790M (rs121434569) mutation [Articles:15737014, 15728811, 21430269, 18093943, 16258541, 17020982, 17085664, 18981003, 18992959, 19381876, 19589612, 20129249, 21248300, 21921847]. This mutation may reduce the binding capability of TKIs to the TK domain of EGFR by an allosteric mechanism [Article:15728811] and increase the affinity to ATP that requires much higher concentration of TKIs to inhibit EGFR [Article:18227510]. The T790M mutation was originally thought to be acquired by tumors cells during treatment with TKIs, however, when more sensitive methods were used for mutation detection, the presence of T790M mutation was shown in a small fraction of tumors cells before treatment with TKIs and usually co-exists in these cells with other activating mutations [Articles:21248300, 16912157]. The tumor cell clones carrying both the activating and the T790M mutations will eventually develop resistance to the TKIs and will be responsible for the progression or recurrence of the disease, this hypothesis was confirmed in which patients harboring T790M mutation before the start of the treatment had a significantly shorter PFS [Articles:22215752, 21233402, 18596266] and decreased response rate (RR) [Article:16912157] compared with those not having T790M mutation.

The T790M (rs121434569) mutation, along with other secondary mutations in EGFR, was observed as a germline mutation in four siblings of European descent family in which multiple members developed NSCLC [Article:16258541]. Neither T790M mutation was observed in a cohort of ~400 subjects [Article:16258541], nor dbSNP (build 137) presented its existence in general population.

Other resistance mechanism to EGFR-targeted therapy:The T790M mutation is detectable in about 50% of patients with NSCLC patients who develop resistance to TKIs treatment [Articles:21430269, 18093943, 21248300], and may not explain all resistance cases. One of the mechanisms of resistance to TKIs involves the MET gene amplification that occurs 5-20% of patients [Article:17463250]. MET gene amplification leads to EGFR-independent activation of the PI3K/AKT pathway through MET/ErbB-3 heterodimers and may be responsible for the resistance to TKIs [Article:17463250]. MET amplification in NSCLC was identified in a very small proportion of tumor cells even before exposure to TKIs and this population of cells expands following TKIs treatment [Article:20129249]. The other mechanism involves the KRAS oncogene, which is mutated in approximately 15-30% of NSCLC [Article:16043828]. Mutations in KRAS and those in EGFR seem to be mutually exclusive, and KRAS mutation harboring patients do not respond to TKI therapy [Article:18804418]. KRAS is a downstream mediator of EGFR-induced cell signaling, and mutations confer constitutive activation of the signaling pathway(s), independent of EGFR activation [Article:19636327]. Additional potential mechanisms of resistance to TKIs have been also identified [Article:23022519]. Thus, NSCLC has a significant level of plasticity, being able to activate several different mechanisms leading to resistance to EGFR-TKIs.

EGFR gene copy number and protein expression in NSCLC:Mutations, gene copy number, and protein expression are three EGFR-related biomarkers that have been extensively studied in clinical trials in order to obtain better predictive and prognostic values for treatment modalities. Although EGFR gene amplification frequently correlates with EGFR protein overexpression and tumor progression [Article:18381415], EGFR gene amplification and protein overexpression studies yielded controversial results in terms of prognostic significance and clinical benefits [Articles:22594511, 23022519, 21969500]. In this respect, the IPASS study (>1200 NSCLC patients) is a cornerstone trial in the assessment of biomarkers associated with EGFR-TKIs activity [Article:21670455]. EGFR mutations are the strongest predictive biomarker for PFS and objective RR to first-line gefitinib versus carboplatin/paclitaxel treatment and post hoc analysis suggested that the predictive value of EGFR gene copy number was driven by coexisting EGFR mutation [Article:21670455].

Germline SNPs:

EGFR contains over 800 SNPs found in >= 1% of samples (dbSNP build 137) and a few of them may have some biological importance.Intron 1 (CA)n repeat (rs11568315): This is a simple sequence repeat polymorphism, dinucleotides range from 9 to 23, with majority clustered around 15 to 21 CA repeats (dbSNP build 137). Association of intron 1 CA repeat polymorphism to better clinical response in NSCLC patients treated with gefitinib was analyzed in four different studies, all has less than 100 study subjects [Articles:17375033, 19201048, 19473722, 17597605]. 16 or fewer CA repeats were considered short and combined together and, 17 or more CA repeats were considered long. NSCLC patients carrying one or two short alleles are more likely to have better clinical response (increased RR, increased PFS and increased OS) when treated with gefitinib as compared to patients who have two long alleles [Articles:17375033, 19201048, 19473722, 17597605]. Well-powered studies are needed to replicate the beneficial clinical effect of rs11568315 in NSCLC patients.

The -216G>T (rs712829): Patients with GT+TT genotypes are associated with increased PFS time when treated with gefitinib in NSCLC patients [Article:17375033] and, decreased severity of diarrhea when treated with erlotinib in neoplasm patients [Article:18309947] as compared patients with GG genotypes. Both studies involved few patients and well-powered studies are needed to replicate suggested associations [Articles:17375033, 18309947].

GWAS studies on tumor risk and EGFR: Two well-powered genome wide association studies (GWAS) showed that SNPs in EGFR were significantly associated to risk of glioma, most common primary brain tumors [Articles:21531791, 22886559], implications of these finding on treatment of glioma or other cancers are yet to be seen.

Conclusion

Extensive molecular, cancer genome sequencing and recent GWAS studies showed that EGFR is an important gene for many biological process and tumorigenesis. Better clinical output can be obtained in NSCLC patients who are harboring activating somatic EGFR mutations who are treated with TKIs. Nevertheless, additional therapies are needed for those patients who are wild type for the EGFR gene. Clinical & treatment associations with germline EGFR SNPs are not strong, more studies are necessary to clarify the role of germline SNPs in treatment of NSCLC.